Astrocytoma is the most common malignant brain tumor in humans and is currently incurable due to its diffusely infiltrative behavior. We have developed a mouse model of astrocytoma that recapitulates the infiltrative behavior of human astrocytoma. In this mouse model the tumor suppressor genes Nf1 and p53 are mutated. Because both NF1 and p53 are frequently mutated in sporadic glioblastoma (GBM), this mouse model is a powerful tool for understanding the biology of tumors associated with neurofibromatosis type 1, as well as sporadic anaplastic astrocytomas and glioblastomas. We are using this mouse model to examine the signal transduction pathways necessary for proliferation and migration of astrocytoma cells both in vivo and in vitro. An understanding of these mechanisms will lead to the development of new therapies for astrocytoma.During fiscal year 2012, we focused on the role of the transcription factor, Cdca7l, on cell proliferation and cell death. This gene is a candidate for the Arlm1 modifier we identified in Project 1, and has been shown by others to interact with the oncogene myc. It also plays a normal role in the brain regulating MAO and downstream catecholamine pathways. Because these catecholamine pathways have been extensively targeted for psychotherapy, we are examining the potential role of these pathways in driving or inhibiting brain cancer.In addition to these cell-based studies, we have been extending our in vitro studies on PDGFR to in vivo studies. We are currently examining how loss of PDGFR in the astrocyte lineage affects the development of astrocytoma and glioblastoma in our Nf1/p53 mouse model. We are aging mice for this study and examining their brain tumor phenotype for whether they develop fewer tumors or whether the tumors develop with overexpression of a different receptor tyrosine kinase, such as EGFR.